P1394: RITUXIMAB BASED LYMPHODEPLETION MAY INCREASE ENGRAFTMENT AND EFFICACY OF SECOND INFUSIONS OF CART19 CELLS IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA.
Authors: Valentín Ortiz-Maldonado, Nuria Martinez-Cibrian, Marta Español-Rego, Guillermo Muñoz-Sanchez, Sergio Navarro, Leticia Alserawan, Maria Castella, Daniel Benitez-Ribas, Laura Magnano, Eva Gine, Luis Gerardo Rodríguez Lobato, Alexandra Martínez Roca, Helena Brillembourg, Mercedes Montoro, Pilar Ayora, Carlos Fernandez de Larrea, Mariona Pascal, Jordi Esteve, Avaro Urbano Ispizua, Manel Juan, Julio Delgado
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Prognosis of relapsed/refractory (R/R) B-cell acute lymphoid leukemia (ALL) is poor, particularly after allogeneic hematopoietic cell transplantation (alloHCT) as well as after CD19-targeted CAR T-cell therapy (CART19). In this setting, few studies have analyzed the feasibility of second CART19 infusions, with most studies reporting very low and brief responses. These suboptimal outcomes of second CART19 infusions have been associated with lower CAR-T expansion/persistence and/or B-cell aplasia duration, as well as the development of humoral (HAMAs) immunogenicity against CAR T-cells. This may be due to, not only T-cell exhaustion, but also due to an immune-mediated rejection of the engraftment. Aims: To evaluate the feasibility of second CART19 administrations in ALL with adapted lymphodepletion regimen. Methods: We report outcomes of 2nd ARI-0001 CART19 infusion in adult ALL patients that relapsed after initial CR. All reported 2nd infusions were administered within a compassionate use program in a single center, from Jul 2017 to Apr 2022. CRS and ICANS were analyzed according with the ASTCT 2019 consensus grading guidelines. Efficacy was analyzed using the NCCN v1.2020 criteria. Results: A total of 12 adult patients with R/R ALL that relapsed after ARI-0001 CART19 received 2nd ARI-0001 infusions. Median age at 1st and 2nd infusion was 33.5 (20-66) and 34 years (21-67), respectively, including 33% (4/12) men. At 1st infusion patients had a median of 4 prior treatment lines (3-6), including inotuzumab 67% (8/12), and alloHCT 92% (11/12). Median bone marrow blast count prior lymphodepletion (LD) was 3% (0-96) and 2% (0-8) for 1st and 2ns infusions, respectively. All patients received LD with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2), but all 2nd infusions (except 1) also included rituximab on day -6 (375 mg/m2). Patients received a median of 1 (0.5-1) and 3 (0.5-3) x106 ARI-0001 cells/kg for 1st and 2nd infusions, respectively. Any grade CRS occurred in 58% (7/12) and 42% (5/12) for 1st and 2nd infusions, respectively. There was no severe CRS nor any grade ICANS or procedure-related mortality events reported for both groups. Complete response-rates after CART19 were seen in 100% (12/12) and 67% (8/12) for 1st and 2nd infusions, respectively. Median PFS was 11.6 and 5.2 months after 1st and 2nd infusions, respectively. Median duration of B-cell aplasia was 2.3 (1.4-12) and 3 (0-NR) months after 1st and 2nd infusions, respectively. Among responders after 2nd infusions (8/12), half of them remain in remission (4/8) at month +30, +28, +15 and +11, tree of which 2nd remission is already lasting longer than their 1st one without further treatment (figure 1). All three stand-alone long-term remissions were associated with negative HAMAs, whereas 71% of R/R to 2nd infusions were positive.Figure 1. Summary/Conclusion: Second ARI-0001 CART19 infusions with prior rituximab based lymphodepletion was able to achieve long term remissions in a subset of patients. Adding rituximab may lead to partial protection to humoral-mediated rejection of second CART19 administrations. Keywords: CAR-T, Rituximab, ALL